paraproteinaemia (pp)€¦ · monoclonal an7bodies or immunoglobulins in serum, csf and urine. •...
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Paraproteinaemia(PP)PresentedbyMohsenAl-Saleh
StaffID#6837SeniorBMS,BScinMLS2004,MScinClin.Chem.2013
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Outline
• Defini3on• Incidenceofparaproteinemia• Disordersthatassociatedwithparaproteinemia• Indica3onofscreeningforparaproteinemia• Inves3ga3onofparaproteinemia• MGUS,mul3plemyeloma
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Defini3on
• A paraprotein is a monoclonal immunoglobulin orimmunoglobulin light chain (Bence Jones protein)presentinthebloodorurineandarisingfromclonalprolifera7on of mature B-cells, most commonlyplasmacellsorB-lymphocytes.
• Alterna7vetermsincludemonoclonalproteinorM-band.
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Immunoglobulins
• HeavyChains:-IgG,IgA-IgM,IgD• LightChains:-Kappa(Κ)-Lambda(λ)
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Immunoglobulins
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Immunoglobulins
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IincidenceofParaproteinaemia
• Elderly>Young• Inindividualsaged>50yrstheoverallincidenceis(3.2%)• Thosewithage>70yrsis(5.3%)
• Men>women(4.0%:2.7%)
• AfricanAmericans>Caucasians
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Consequences of paraproteinemia
• Increasedserumviscosity• Highserumproteins(>TP)concentra:on• Pseudo-hyponatraemia• BenceJonesprotein:
• foundintheurineofpaJentwithB-cellmalignancy• ConsistsoffreemonoclonalL-chainsortheirfragments• LowMW(20-40kDa)
• Amyloidosiscanalsooccur
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Disordersassociatedwithparaproteinemia
MayoClinicReports:• Experience• 1684ptwithPP• KyleandKumar,Bri3sh• JournalofHaematology
2007;139,730–743
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1. MalignantB-celldisorder:
• Mul7plemyeloma(IgG,IgA,IgD,IgMor,λ,Κfreelightchains)
2. MGUS:
• ParaproteindetectedwithnoevidenceofotherB-celldisorder
Disorderassociatedwithaparaprotein
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Indica3onoftes3ngofPP
• Mul7plemyelomasuspected• Bothurineandbloodshouldbescreened• Pa7entshouldbescreenedforpresenceofM-proteinwhenpresen7ngwithanyoftheclinicalfindingslistedbelow:
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ClinicalIndica3onsforscreeningforM-protein
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Inves3ga3onofparaproteinemia
• Serumproteinelectrophoresis(SPE)• Serumimmunofixa7onelectrophoresis(IFE)• Serumfreelightchain(SFLCA)• Quan7ta7veImmunoglobulins
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Serum&urineproteinelectrophoresis
SPE:• Semi-Quan7ta7ve• M-bandquan7fica7onUPE:• Qualita7ve• Requires24hrsurinecollec7on
Immunoglobulinlevels:• IgA,IgG,IgM,IgD
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Serum&urineproteinelectrophoresis
Advantages:• Simple,cheap• Commerciallyproducedgels
• Mul7plesamplesinparallelonthesamegel
• Lowamountofsample
Disadvantages:• Lowresolu7on• Notfullyautomated• Timeconsuming• Gelmustbestainedtovisualize
• Semi-quan7ta7ve• Maxi.Voltsused100v
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Immunofixa3on(IFE)
• Permitsthedetec7onandtypingofmonoclonalan7bodiesorImmunoglobulinsinserum,CSFandurine.
• Principle:• Themethoddetectsbyprecipita7on:whensolubleAgisbroughtincontactwithcorrespondingAb,precipita7onoccurs,whichmaybevisibleonlyaaerstaining.
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IFE:• Qualita7ve
• Iden7fiesheavychain(IgG,IgA,IgM,IgD,IgE)
• Iden7fieslightchain(λ,κprotein)type
Immunofixa3on(IFE)
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Immunofixa3ontendstoreplaceproteinelectrophoresis
• Itisfaster• Itissomewhatmoresensi7veandrevealanimmunoglobulinesatlowerconcentra7on(lessthan1gm/L)
• Itcanbepar7allyautomated• Itismoreeasilyreadandinterpreted
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SerumFreelightchain(SFLC)
• Dailyproduc7on0.5-1gm• Freelyfilteredbyglomeruli• Reabsorbedbyproximaltubules• Halflife3-6hrs
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SerumFreeLightChain(SFLC)
• AssaydetectsonlyfreeLC• Quan7ta7ve• CandetectmildlyincreasedlevelsofFLCevenwhentheselevelsareundetectablebySPEPandIFE
• ExcellentforfollowingdiseaseprogressioninMGUS,anddiseaseresponseinmyeloma
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TheKappa/LambdaRa3o
• Whenthelevelofeitherkappaorlambdaisveryhighandtheotherchainisnormalorlow,thenthera7oisabnormalàmyelomaisac7ve
• Iflevelsofbothkappaandlambdaareincreased,thera7omaybewithinthenormalrangeàindicatesadiseaseotherthanmyeloma,suchaspoorkidneyfunc7on
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• Ifthekappaandlambdalevelsarebothwithinthenormalrange,some7mesthera7omaybeabnormalàpersistentlowlevelofac7vemyelomawithexcessproduc7onoftheabnormallightchains.
• Normalkappa/lambdara7oaaertreatmentàgoodremission
TheKappa/LambdaRa3o
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OnceaPPisfoundwhatfurtherworkup
shouldbeperformed?• DependingonclinicalsingsandsymptomsandontypesofM-
protein(IgG,IgA,IgM,IgD)inden7fiedbyIFE:DifferenJalDxIgM:• Waldenstromsmacroglobulinaemia(WM)• Chroniclymphoidleukemia(CLL)• Non-hodgkinslymphoma(NHL)• Monoclonalgammopathyofundeterminedsignificance(MGUS)• Amyloidosis
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DxofhighIgA:• GammaAmyloma• Chronicinfec7on• Chronicliverdisease• Sarcoidosis• RA• SLE
DxofhighIgG:• IgGmyloma• Chronicinfec7on• Chronicliverdiseases• Sarcoidosis• Autoimmunedisease• Parasi7cdiseases
OnceaPPisfoundwhatfurtherworkup
shouldbeperformed?
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DisordersassociatedwithM-protein
Pa7entswithplasmacelldisorderandacircula7ngparaproteinissubdivideintothreegroups:
• MGUS• Asymptoma7cmyeloma(previouslytermedindolentorequivocalmyeloma)
• Symptoma7cmyeloma
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Threevariablesdefinethesegroups:(1)M-proteinlevel(2)bonemarrowplasmacellpercentage(3)thepresenceorabsenceofmyelomarelatedorganor7ssueimpairment(ROTI)
DisordersassociatedwithM-protein
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Monoclonalgammopathyofundeterminedsignificant(MGUS)
• Usualpresenta7onisasymptoma7celeva7onoftotalprotein
Diagnosisofexclusion:• R/OMyeloma• R/Ootherplasmacellabnormali7es• theriskofprogressionofMGUStomyelomaorrelateddisorderis1%peryear
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• Notfoundinchildren• Commonovertheageof50yrs• Riskincreased3.7foldshigherforindividualswith1stdegreerelaJvewithdisease
Monoclonalgammopathyofundeterminedsignificant(MGUS)
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Mul3pleMyloma(MM)
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• 1%ofallmalignancies• 10%ofhematologicalmalignancies(2ndmostcommon)• 3-4per100,000populaJon• 16,000newcases/yr;11,000deaths/yr• M>F• Risk:radiaJonexposure
Mul3pleMyeloma
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Symptoms
• Bonepain(70%)• Hypercalcaemia(30%)• Fever(15%)• Renalfailure(20%)• InfecJon(10%)• normochromicnormocyJcanemia(66%)• Peripheralneuropathy• Hyperviscosity• ImpairedcoagulaJon• ItcanbesummariesasCRAB
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Paraprotein picture in MM
• Serum/urineparaproJneseenin97%ofMMatdiagnosis
• 75%ofMMpaJenthaveBJPsintheirurine• 80%haveaserumM-protein&canbeidenJfiedonSPE• >90%haveanM-proteinidenJfiedviaserumIFE(somearehiddeninothernormalbands)
• 15-20%ofMMproducelightchainsonly,whichmaynotbepresentinserumandpresentedonlyinurine
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TypesofmonoclonalproteinsinMM
• BasedonIGisotypeswithfrequencyparalleltonormalserumpercentages– IgGkappa(30%)orlambda(18%)– IgAkappa(10%)orlambda(6%)– Freekappaorlambda(15%to20%)
• Bence-Jonesproteins– IgM(<1%)– IgD(<1%)– IgE(<1%)
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RxofMul3pleMyeloma
• NocureforMM• Mediansurvival7me:– StageI
• 60months– StageII
• 45months– StageIII
• 30months
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Treatmentop3onforMul3pleMyeloma• Chemotherapy:
• Immunotherapy:
– Thalidomide(Thalomid)– Lenalidomide(Revlumid)– Bortezomib(Velcade)
• Cor3costeroids:
– Prednizone
• Stemcelltransplanta3on:
– Autologous– Allogenic
• Radia3ontherapy:
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Cases
• Case1:• 71yrsmalehas• targetorgandamage(anemia,renalfailureandbonylyJclesion
• MRIshowedinfiltraJonofT5,T12,L5• BM:plasmacellof30%
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IFEElectrophoresis
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Case2:• 37yrsoldfemalediagnosedonMay2013tohaveplasmacellmyeloma.presentedtohospitalhavinglowerbackpain.MRIdoneshowedmulJplesacrallesion.
• BMdoneshowed20%plasmacellwithCD138expression
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THANKYOU